β-Amyloid Disrupts Activity-Dependent Gene Transcription Required for Memory through the CREB Coactivator CRTC1
β-Amyloid Disrupts Activity-Dependent Gene Transcription Required for Memory through the CREB Coactivator CRTC1
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DOI：
10.1523/jneurosci.2154-10.2010
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发表时间：
2010-07-14
影响因子：
5.3
通讯作者：
Saura, Carlos A.
中科院分区：
文献类型：
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作者：
Espana, Judit;Valero, Jorge;Saura, Carlos A.
活动依赖性基因表达介导的突触效能的变化是重要的记忆储存，但在年龄相关的记忆障碍的基因转录变化的机制知之甚少。在这项研究中，我们报告说，cAMP反应元件结合蛋白（CREB）调节的转录辅激活因子CRTC 1介导的基因转录受损的神经元和大脑从阿尔茨海默氏病（A β）转基因小鼠表达的人β-淀粉样前体蛋白（APP（Sw，Ind））。β-淀粉样蛋白（A β）对cAMP和Ca 2+信号应答的CRTC 1依赖性基因转录的抑制通过钙内流减少和PP 2B/钙调神经磷酸酶依赖性CRTC 1 Ser 151去磷酸化的破坏介导。一致地，CRTC 1或活性CRTC 1 S151 A和钙调磷酸酶突变体的表达逆转了APPSw，Ind神经元中CRTC 1转录活性的缺陷。通过药理学阻断L型电压门控钙通道（VGCC）而不是通过阻断NMDA或AMPA受体来抑制钙内流，模拟了APP（Sw，Ind）神经元中观察到的CRTC 1转录活性的降低，而L型VGCC的激动剂有效地逆转了这些缺陷。与CRTC 1在A β诱导的突触和记忆功能障碍中的作用一致，我们证明了与APP（Sw，Ind）小鼠中与记忆相关的CRTC 1依赖性基因（Bdnf，c-fos和Nr 4a 2）的选择性减少与海马依赖性空间记忆缺陷一致。这些发现表明，CRTC 1在将突触活动与突触依赖性记忆所需的基因转录偶联中起着关键作用，并且A β可以通过影响CRTC 1功能来破坏认知。
Activity-dependent gene expression mediating changes of synaptic efficacy is important for memory storage, but the mechanisms underlying gene transcriptional changes in age-related memory disorders are poorly understood. In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription coactivator CRTC1 is impaired in neurons and brain from an Alzheimer's disease (A beta) transgenic mouse expressing the human beta-amyloid precursor protein (APP(Sw,Ind)). Suppression of CRTC1-dependent gene transcription by beta-amyloid (A beta) in response to cAMP and Ca2+ signals is mediated by reduced calcium influx and disruption of PP2B/calcineurin-dependentCRTC1dephosphorylation at Ser151. Consistently, expression of CRTC1 or active CRTC1 S151A and calcineurin mutants reverse the deficits on CRTC1 transcriptional activity in APPSw, Ind neurons. Inhibition of calcium influx by pharmacological blockade of L-type voltage-gated calcium channels (VGCCs), but not by blocking NMDA or AMPA receptors, mimics the decrease on CRTC1 transcriptional activity observed in APP(Sw,Ind) neurons, whereas agonists of L-type VGCCs reverse efficiently these deficits. Consistent with a role of CRTC1 on A beta-induced synaptic and memory dysfunction, we demonstrate a selective reduction of CRTC1-dependent genes related to memory (Bdnf, c-fos, and Nr4a2) coinciding with hippocampal-dependent spatial memory deficits in APP(Sw,Ind) mice. These findings suggest that CRTC1 plays a key role in coupling synaptic activity to gene transcription required for hippocampal-dependent memory, and that A beta could disrupt cognition by affecting CRTC1 function.